The earliest events following mucosal HIV-1 exposure represent a critical window of opportunity for vaccine-elicited immune responses to impact the acquisition and propagation of HlV-1 infection. However, opportunities to elucidate these early immunologic and virologic events in humans are extremely limited. Modeling these events in nonhuman primates will therefore likely be instrumental in the design and development of next generation HIV-1 vaccine strategies. Such studies will provide critical insights into the early events of virus transmission and the capacity of vaccine-elicited immune responses to block or to attenuate these events. In this Consortium, we have assembled many the of world's foremost experts in nonhuman primate research and HIV-1 vaccine development to analyze the virology and immunology of early SIV/SHIV infection in rhesus monkeys as well as to determine the mechanism by which cutting-edge vaccine approaches afford protection in these models. These studies will allow a detailed interrogation of the ability of different types of immune responses to intercept the virus and to control early infection. We hypothesize that certain vaccines and immunologic interventions will be able to attenuate or even abrogate the early events following mucosal SIV/SHIV infection, including the initial local amplification of virus at the mucosal portal of entry as well as the subsequent trajectory of virus spread that leads to systemic dissemination. During the proposed five year project period, we will explore in detail the mechanism of protection afforded by adenovirus vectors and poxvirus vectors (Barouch, Project 1), cytomegalovirus vectors (Picker, Project 2), live attenuated SIV (Johnson, Project 3), neutralizing antibodies (Burton, Project 4), and adeno-associated virus-mediated antibody delivery (Desrosiers, Project 5). These Projects will receive extensive support from the Administrative/Biostatistics (Barouch/Johnson, Core A), Pathology (Haase, Core B), Immunology (Johnson/Burton, Core C), Virology (Shaw/Lifson, Core D), Systems Biology (Sekaly, Core E), and Nonhuman Primate (Axthelm/Mansfield, Core F) core facilities. PUBLIC HEALTH RELEVANCE: The earliest events of mucosal HIV-1 infection in humans remain largely undefined, given the short duration and asymptomatic nature of the eclipse phase of HIV-1 infection. An improved understanding of the earliest events following mucosal SIV/SHIV infection of rhesus monkeys will yield insights into critical viral vulnerabilities during the transmission process that can be exploited by vaccine-elicited immune responses. Such knowledge will lead to the development of improved next generation HlV-1 vaccine strategies.